Various publications are referred to in parentheses throughout this application. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Prostaglandins (PGs) are synthesized from arachidonic acid by cyclooxygenases (COX1 and COX2) and corresponding synthases (Helliwell et al. 2004). PGs play an important role in physiology and clinical settings. Their biological effects include triggering inflammation, fever and pain (Blatteis and Sehic, 1997; Bley et al., 1998; Vanegas and Schaible, 2001; Samad et al., 2002); induction of labor (Ulmann et al., 1992); modulation of renal hemodynamics and of water and solute reabsorption (Epstein, 1986; Wang et al., 1998; Yokoyama et al., 2002); arterial vasodilatation (Clyman et al., 1978; Coceani and Olley, 1988; Smith et al., 1994); stimulation of cell proliferation and angiogenesis (Ferrara et al, 1997; Tsujii et al, 1998; Young, 2004; Mann et al, 2006; Sheng et al, 2001; Shao et al, 2006); and mediating sensitization of sensory neurons (Southall and Vasko, 2000; Southall and Vasko, 2001; Seybold et al., 2003). PG analogues, such as latanoprost and unoprostone, have been used to treat glaucoma (Stjernschantz, 1995; Alm, 1998; Susanna et al., 2002; Stjernschantz, 2004). At the cellular level, PGs are involved in several major signaling pathways, including the mitogen-activated protein (MAP) kinase and protein kinase A pathways by upregulation of cAMP (Narumiya et al., 1999; Bos et al., 2004).
The magnitude of PG effects depends not only on their production but also their metabolism. The prostaglandin transporter (PGT) (Kanai et al., 1995; U.S. Pat. No. 5,792,851) removes PGs from the extracellular compartment and thereby terminates their interactions with receptors on cell membranes. PGT delivers PGs to cytoplasmic 15-OH PG dehydrogenase (Schuster, 2002; Nomura et al., 2004), resulting in oxidation and inactivation. Because PGT is highly expressed in the tissues and organs where PGs are synthesized (Bao et al., 2002), and because PGT regulates a broad and complex PG signaling system, inhibitors of PGT are important for manipulating signaling. Inhibition of PGT lowers blood pressure by vasodilation and natriuresis and inhibits platelet aggregation.
Known PGT blockers include inhibitors of the organic anion transporters (OATs), such as bromcresol green and bromosulfophthalein, and some COX2 inhibitors, such as indomethacin and ibuprofen (Bito and Salvador, 1976; Kanai et al., 1995). One of the main problems with these inhibitors is that they are not specific for PGT (Jacquemin et al., 1994; Sweet et al., 1997). Recently, specific PGT inhibitors have been developed (Chi et al., 2005; WO 2007/136638; US 2012/0238577).
Obesity is a world-wide epidemic associated with significant morbidity and mortality which costs billions of dollars per year (e.g., Carter et al., 2012; Holes-Lewis et al., 2013; Santo-Domingo et al. 2012). The need for more effective medications and treatments remains clear.
Pulmonary arterial hypertension (PAH) is a chronic progressive disease of the pulmonary vasculature characterized by elevated pulmonary arterial pressure and secondary right ventricular failure, with an estimated incidence of 1-2 cases per 1 million persons in the general population (Patel et al., 2012). Despite advances in diagnosis and treatment, new therapeutic strategies are urgently required (Agarwal and Gomberg-Maitland, 2012; Yao, 2012).
The present invention addresses the need for treatments for pulmonary arterial hypertension and obesity, using inhibitors of PGT.